FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that promotes renal phosphate excretion. Serum FGF23 is increased in chronic kidney disease (CKD) and contributes to pathologic cardiac hypertrophy by activating FGF receptor (FGFR) 4 on cardiac myocytes, which might lead to the high cardiovascular mortality in CKD patients. Increases in serum FGF23 levels have also been observed following endurance exercise and in pregnancy, which are scenarios of physiologic cardiac hypertrophy as an adaptive response of the heart to increased demand. To determine whether FGF23/FGFR4 contributes to physiologic cardiac hypertrophy, we studied FGFR4 knockout mice (FGFR4-/-) during late pregnancy. In comparison to virgin littermates, pregnant wild-type and FGFR4-/- mice showed increases in serum FGF23 levels and heart weight; however, the elevation in myocyte area observed in pregnant wild-type mice was abrogated in pregnant FGFR4-/- mice. This outcome was supported by treatments of cultured cardiac myocytes with serum from fed Burmese pythons, another model of physiologic hypertrophy, where the co-treatment with an FGFR4-specific inhibitor abrogated the serum-induced increase in cell area. Interestingly, we found that in pregnant mice, the heart, and not the bone, shows elevated FGF23 expression, and that increases in serum FGF23 are not accompanied by changes in phosphate metabolism. Our study suggests that in physiologic cardiac hypertrophy, the heart produces FGF23 that contributes to hypertrophic growth of cardiac myocytes in a paracrine and FGFR4-dependent manner, and that the kidney does not respond to heart-derived FGF23.

High phosphate-induced progressive proximal tubular injury is associated with the activation of Stat3/Kim-1 signaling pathway and macrophage recruitment.

Dietary phosphate intake in the Western population greatly exceeds the recommended dietary allowance and is linked to enhanced cardiovascular and all-cause mortality. It is unclear whether a chronic high phosphate diet (HPD) causes kidney injury in healthy individuals. Here, we show that feeding a 2% HPD in C57BL/6N mice for one up to six months resulted in hyperphosphatemia, hyperphosphaturia, increased plasma levels of fibroblast growth factor (FGF) 23, and parathyroid hormone (PTH) compared to mice on a 0.8% phosphate diet. Kidney injury was already noted after two months of HPD characterized by loss of proximal tubular (PT) cell polarity, flattened epithelia, disruption of brush border membranes, vacuolization, increased PT cell proliferation, marked interstitial mononuclear infiltration, and progressive accumulation of collagen fibers. HPD increased Stat3 activation and Kim-1 expression in PT epithelial cells and enhanced renal synthesis of chemokines recruiting monocytes and macrophages as well as macrophage related factors. Enhanced recruitment of F4/80+ macrophages around injured PT lesions was timely associated with increased Kim-1 synthesis, tubular MCP-1 expression, and degree of PT injury score. Likewise, tubulointerstitial fibrosis was associated with activation of Stat3/Kim-1 signaling pathway. The stimulation of human proximal tubular cells with high phosphate activated Stat3 signaling and induced HAVCR1 and CCL2 expression. We conclude that high phosphate results in progressive proximal tubular injury, indicating that high dietary phosphate intake may affect kidney health and therefore represents an underestimated health problem for the general population.

Phosphate Is a Cardiovascular Toxin.

Phosphate is essential for proper cell function by providing the fundamentals for DNA, cellular structure, signaling and energy production. The homeostasis of phosphate is regulated by the phosphaturic hormones fibroblast growth factor (FGF) 23 and parathyroid hormone (PTH). Recent studies indicate that phosphate induces phosphate sensing mechanisms via binding to surface receptors and phosphate cotransporters leading to feedback loops for additional regulation of serum phosphate concentrations as well as by phosphate itself. An imbalance to either side, enhances or reduces serum phosphate levels, respectively. The latter is associated with increased risk for cardiovascular diseases and mortality. Hyperphosphatemia is often due to impaired kidney function and linked to vascular disease, hypertension and left ventricular hypertrophy. In contrast, hypophosphatemia either due to reduced dietary intake or intestinal absorption of phosphate or hereditary or acquired renal phosphate wasting, may result in impaired energy metabolism and cardiac arrhythmias. Here, we review the effects and its underlying mechanisms of deregulated serum phosphate concentrations on the cardiovascular system. Finally, we summarize the current therapeutic approaches for both lowering serum phosphate levels and improvement of cardiovascular disease.

Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice.

Fibroblast growth factor (FGF) 23 is elevated in chronic kidney disease (CKD) to maintain phosphate homeostasis. FGF23 is associated with left ventricular hypertrophy (LVH) in CKD and induces LVH via klotho-independent FGFR4-mediated activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling in animal models, displaying systemic alterations possibly contributing to heart injury. Whether elevated FGF23 per se causes LVH in healthy animals is unknown. By generating a mouse model with high intra-cardiac Fgf23 synthesis using an adeno-associated virus (AAV) expressing murine Fgf23 (AAV-Fgf23) under the control of the cardiac troponin T promoter, we investigated how cardiac Fgf23 affects cardiac remodeling and function in C57BL/6 wild-type mice. We report that AAV-Fgf23 mice showed increased cardiac-specific Fgf23 mRNA expression and synthesis of full-length intact Fgf23 (iFgf23) protein. Circulating total and iFgf23 levels were significantly elevated in AAV-Fgf23 mice compared to controls with no difference in bone Fgf23 expression, suggesting a cardiac origin. Serum of AAV-Fgf23 mice stimulated hypertrophic growth of neonatal rat ventricular myocytes (NRVM) and induced pro-hypertrophic NFAT target genes in klotho-free culture conditions in vitro. Further analysis revealed that renal Fgfr1/klotho/extracellular signal-regulated kinases 1/2 signaling was activated in AAV-Fgf23 mice, resulting in downregulation of sodium-phosphate cotransporter NaPi2a and NaPi2c and suppression of Cyp27b1, further supporting the bioactivity of cardiac-derived iFgf23. Of interest, no LVH, LV fibrosis, or impaired cardiac function was observed in klotho sufficient AAV-Fgf23 mice. Verified in NRVM, we show that co-stimulation with soluble klotho prevented Fgf23-induced cellular hypertrophy, supporting the hypothesis that high cardiac Fgf23 does not act cardiotoxic in the presence of its physiological cofactor klotho. In conclusion, chronic exposure to elevated cardiac iFgf23 does not induce LVH in healthy mice, suggesting that Fgf23 excess per se does not tackle the heart.

Comprehensive Expression Analysis of Cardiac Fibroblast Growth Factor 23 in Health and Pressure-induced Cardiac Hypertrophy.

Enhanced fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney and heart disease. Experimentally, FGF23 directly induces cardiac hypertrophy and vice versa cardiac hypertrophy stimulates FGF23. Besides the bone, FGF23 is expressed by cardiac myocytes, whereas its synthesis in other cardiac cell types and its paracrine role in the heart in health and disease is unknown. By co-immunofluorescence staining of heart tissue of wild-type mice, we show that Fgf23 is expressed by cardiac myocytes, fibroblasts and endothelial cells. Cardiac Fgf23 mRNA and protein level increases from neonatal to six months of age, whereas no age-related changes in bone Fgf23 mRNA expression were noted. Cardiac myocyte-specific disruption of Fgf23 using Cre-LoxP system (Fgf23fl/fl/cre+) caused enhanced mortality, but no differences in cardiac function or structure. Although pressure overload-induced cardiac hypertrophy induced by transverse aortic constriction (TAC) resulted in a slightly worse phenotype with a more severe reduced ejection fraction, higher end-systolic volume and more enlarged systolic LV diameter in Fgf23fl/fl/cre+ mice compared to controls, this was not translated to any worse cellular hypertrophy, fibrosis or chamber remodeling. TAC induced Fgf23 mRNA expression in whole cardiac tissue in both genotypes. Interestingly, co-immunofluorescence staining revealed enhanced Fgf23 synthesis in cardiac fibroblasts and endothelial cells but not in cardiac myocytes. RNA sequencing of isolated adult cardiac myocytes, cardiac fibroblasts and endothelial cells confirmed significantly higher Fgf23 transcription in cardiac fibroblasts and endothelial cells after TAC. Our data indicate that Fgf23 is physiologically expressed in various cardiac cell types and that cardiac fibroblasts and endothelial cells might be an important source of FGF23 in pathological conditions. In addition, investigations in Fgf23fl/fl/cre+ mice suggest that cardiac myocyte-derived FGF23 is needed to maintain cardiac function during pressure overload.

FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis.

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin-angiotensin-aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23.

Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal link has not been established so far. Here, we investigated the cardiac phenotype in klotho hypomorphic (kl/kl) mice and Hyp mice, two mouse models of elevated FGF23 levels and klotho deficiency, but differing in parameters of mineral metabolism, by using histology, quantitative real-time PCR, immunoblot analysis, and serum and urine biochemistry. Additionally, the specific impact of calcium, phosphate, PTH, and 1,25D on hypertrophic growth of isolated neonatal rat cardiac myocytes was investigated in vitro. Kl/kl mice displayed high serum Fgf23 levels, increased relative heart weight, enhanced cross-sectional area of individual cardiac myocytes, activated cardiac Fgf23/Fgf receptor (Fgfr) 4/calcineurin/nuclear factor of activated T cell (NFAT) signaling, and induction of pro-hypertrophic NFAT target genes including Rcan1, bMHC, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) as compared to corresponding wild-type (WT) mice. Investigation of fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated ERK1/2 activation and enhanced expression of Tgf-ß1, collagen I, and Mmp2 in kl/kl mice than in WT mice. In contrast, despite significantly elevation of serum and cardiac Fgf23, and reduced renal klotho expression, Hyp mice showed no signs of pathological cardiac remodeling. Kl/kl mice showed enhanced serum calcium and phosphate levels, while Hyp mice showed unchanged serum calcium levels, lower serum phosphate, and elevated serum iPTH concentrations compared to corresponding WT mice. In cultured cardiac myocytes, treatment with both calcium or phosphate significantly upregulated endogenous Fgf23 mRNA expression and stimulated hypertrophic cell growth and expression of pro-hypertrophic genes. The treatment with PTH induced hypertrophic cell growth only, and stimulation with 1,25D had no significant effects. In conclusion, our data indicate that Hyp mice, in contrast to kl/kl mice appear to be protected from pathological cardiac remodeling during conditions of high FGF23 levels and klotho deficiency, which may be due, at least in part, to differences in mineral metabolism alterations, i.e., hypophosphatemia and lack of hypercalcemia.

FGF23 Actions on Target Tissues-With and Without Klotho.

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in "classic" klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23's potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might-at least partially-underlie the pleiotropic tissue-protective functions of klotho.

Fibroblast growth factor 23 is induced by an activated renin-angiotensin-aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts.

Background: Fibroblast growth factor 23 (FGF23) is discussed as a new biomarker of cardiac hypertrophy and mortality in patients with and without chronic kidney disease (CKD). We previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD and induces cardiac hypertrophy via activation of FGF receptor 4 independent of its co-receptor klotho. The impact of FGF23 on cardiac fibrosis is largely unknown. Methods: By conducting a retrospective case-control study including myocardial autopsy samples from 24 patients with end-stage CKD and in vitro studies in cardiac fibroblasts and myocytes, we investigated the pro-fibrotic properties of FGF23. Results: The accumulation of fibrillar collagens I and III was increased in myocardial tissue of CKD patients and correlated with dialysis vintage, klotho deficiency and enhanced cardiac angiotensinogen (AGT) expression. Using human fibrosis RT2 Profiler PCR array analysis, transforming growth factor (TGF)-ß and its related TGF-ß receptor/Smad complexes, extracellular matrix remodeling enzymes and pro-fibrotic growth factors were upregulated in myocardial tissue of CKD patients. FGF23 stimulated cell proliferation, migration, pro-fibrotic TGF-ß receptor/Smad complexes and collagen synthesis in cultured cardiac fibroblasts. In isolated cardiac myocytes, FGF23 enhanced collagen remodeling, expression of pro-inflammatory genes and pro-survival pathways and induced pro-hypertrophic genes. FGF23 stimulated AGT expression in cardiac myocytes and angiotensin II and aldosterone, as components of the renin-angiotensin-aldosterone system (RAAS), induced FGF23 in cardiac myocytes. Conclusions: Our data demonstrate that activated RAAS induces FGF23 expression in cardiac myocytes and thereby stimulates a pro-fibrotic crosstalk between cardiac myocytes and fibroblasts, which may contribute to myocardial fibrosis in CKD.

Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats.

BACKGROUND: Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hypertrophy (LVH). Here, we determined if 1,25-dihydroxyvitamin D (calcitriol) inhibits FGF23-induced cardiac signaling and LVH. METHODS: 5/6 nephrectomized (5/6 Nx) rats were treated with different doses of calcitriol for 4 or 10 weeks and cardiac expression of FGF23/FGFR4 and activation of calcineurin/NFAT as well as LVH were analyzed. FGFR4 activation and hypertrophic cell growth were studied in cultured cardiac myocytes that were co-treated with FGF23 and calcitriol. RESULTS: In 5/6Nx rats with LVH, we detected elevated FGF23 expression in bone and myocardium, increased cardiac expression of FGFR4 and elevated cardiac activation of calcineurin/NFAT signaling. Cardiac expression levels of FGF23 and FGFR4 significantly correlated with the presence of LVH in uremic rats. Treatment with calcitriol reduced LVH as well as cardiac FGFR4 expression and calcineurin/NFAT activation. Bone and cardiac FGF23 expression were further stimulated by calcitriol in a dose-dependent manner, but levels of intact cardiac FGF23 protein were suppressed by high-dose calcitriol. In cultured cardiac myocytes, co-treatment with calcitriol blocked FGF23-induced activation of FGFR4 and hypertrophic cell growth. CONCLUSIONS: Our data suggest that in CKD, cardioprotective effects of calcitriol stem from its inhibitory actions on the cardiac FGF23/FGFR4 system, and based on their counterbalancing effects on cardiac myocytes, high FGF23 and low calcitriol synergistically contribute to cardiac hypertrophy.

Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells.

Chronic kidney disease (CKD) is a state of Klotho deficiency and excess of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Both dysregulations were shown to be associated with endothelial dysfunction in humans, but direct vascular effects of FGF23 remain largely elusive. In vitro experiments were performed to assess the effects of FGF23 (10 ng/mL) in relation to its co-receptor Klotho on nitric oxide (NO) synthesis and reactive oxygen species (ROS) formation and detoxification in human coronary artery endothelial cells (HCAEC). Membrane-bound Klotho is expressed in HCAEC, and FGF23 increases the expression of the Klotho shedding protease ADAM17, and consequently the secretion of soluble Klotho. FGF23 activates FGF receptor 1 and stimulates NO release via Akt-dependent activation of endothelial NO synthase (eNOS). Both FGF receptor (FGFR)-dependent ROS formation via activation of NADPH oxidase 2 (Nox2) as well as ROS degradation via superoxide dismutase 2 (SOD2) and catalase (CAT) is stimulated by FGF23. Pre-incubation with a Klotho inhibitor blunts the FGF23-stimulated Akt-eNOS activation and NO synthesis, and decreases ROS degradation by blocking SOD2 and CAT enzymes, whereas FGF23-stimulated ROS synthesis via Nox2 is unaffected, resulting in low NO bioavailability and increased oxidative stress. Our data indicate that in the presence of Klotho, FGF23 induces NO release in HCAEC and its stimulating effects on ROS production are counterbalanced by increased ROS degradation. In states of Klotho deficiency, e.g., CKD, FGF23-mediated NO synthesis is blunted and ROS formation overrules ROS degradation. Thus, FGF23 excess may primarily promote oxidative stress and thus endothelial dysfunction.

Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously. METHODS: We conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sex-matched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescence microscopy, qRT-PCR and western blotting. RESULTS: The majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant. CONCLUSIONS: Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.

Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.

Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.

Integrin αE(CD103) Is Involved in Regulatory T-Cell Function in Allergic Contact Hypersensitivity.

Murine contact hypersensitivity (CHS) is a dendritic cell (DC)-dependent T-cell-mediated inflammation with CD8+ T cells as effectors and CD4+ T cells as regulators (Treg cells) that models human allergic contact dermatitis. The integrin αE(CD103) is expressed by some T-cell and DC subsets and has been implicated in epithelial lymphocyte localization, but its role in immune regulation remains enigmatic. We have identified a function for CD103 in the development of cutaneous allergic immune responses. CHS responses, but not irritant contact dermatitis, were significantly augmented in CD103-deficient mice in hapten-challenged skin. Phenotype and function of skin DCs during sensitization were normal, whereas adoptive transfer experiments revealed that the elevated CHS response in CD103-deficient mice is transferred by primed T cells and is independent of resident cells in recipient mice. While T-cell counts were elevated in challenged skin of CD103-deficient mice, the FoxP3 expression level of CD4+CD25+ Treg cells was significantly reduced, indicating impaired functionality. Indeed, Treg cells from CD103-deficient mice were not able to suppress CHS reactions during the elicitation phase. Further, CD103 on FoxP3+ Treg cells was involved in Treg retention to inflamed skin. These findings indicate an unexpected dichotomous functional role for CD103 on Treg cells by modulating FoxP3 expression.

Interleukin-1ß interferes with epidermal homeostasis through induction of insulin resistance: implications for psoriasis pathogenesis.

Response pathways of the metabolic and the immune system have been evolutionary conserved, resulting in a high degree of integrated regulation. Insulin is a central player in the metabolic system and potentially also in the homeostasis of the skin. Psoriasis is a frequent and often severe autoimmune skin disease, clinically characterized by altered epidermal homeostasis, of which the molecular pathomechanisms are only little understood. In this study, we have examined a potential role for insulin signaling in the pathogenesis of this disease. We show that IL-1ß is present in high quantities in tissue fluid collected via microdialysis from patients with psoriasis; these levels are reduced under successful anti-psoriatic therapy. Our results suggest that IL-1ß contributes to the disease by dual effects. First, it induces insulin resistance through p38MAPK (mitogen-activated protein kinase), which blocks insulin-dependent differentiation of keratinocytes, and at the same time IL-1ß drives proliferation of keratinocytes, both being hallmarks of psoriasis. Taken together, our findings point toward insulin resistance as a contributing mechanism to the development of psoriasis; this not only drives cardiovascular comorbidities, but also its cutaneous phenotype. Key cytokines inducing insulin resistance in keratinocytes and kinases mediating their effects may represent attractive targets for novel anti-psoriatic therapies.